Lipid-core nanocapsules (LCNs) have been proposed as drug carriers to improve brain delivery by modulating drug pharmacokinetics (PK). However, it is not clear whether the LCNs carry the drug through the blood-brain barrier or increase free drug penetration due to changes in the barrier permeability. Quetiapine (QTP) penetration to the brain is mediated by influx transporters and therefore might be reduced by drug transporters inhibitiors as probenecid. The goal of this work was to investigate the role of type-III LCNs on brain penetration of QTP using microdialysis in the presence probenecid. QTP-loaded LCN (QLNC) was successfully obtained with a small particle size (143 ± 6 nm), low polydispersity index (PI < 0.1), and high encapsulation efficiency (95.4 ± 1.82%.). Total and free drug concentration in plasma and free drug concentration in brain were analyzed following i.v. bolus dosing of nonencapsulated drug (FQ) and QLNC formulations alone and in association with probenecid to male Wistar rats. QTP free plasma fraction right after administration of QLNC was smaller than the fraction observed after FQ dosing; however, it increased over time until similar free drug levels were attained, suggesting that type-III LNCs produce a short in vivo sustained release of the drug. The inhibition of influx transporters by PB led to a reduction of free QTP brain penetration, as observed by the reduction of penetration factor from 1.55 ± 0.17 to a value closer to unit (0.94 ± 0.15). However, when the drug was nanoencapsulated, the inhibition of influx transporters had no effect on the brain penetration factor (0.88 ± 0.21 to 0.92 ± 0.13) probably because QTP is loaded into LNC and not available to interact with transporters. Taken together, these results suggest that LNC type-III carried QTP in the bloodstream and delivered the drug to the brain.
Keywords: BBB transport; lipid-core nanocapsules; microdialysis; quetiapine.